Abstract GLP-1 Agonism for Blocking Cocaine Euphoria and Self-Administration Cocaine addiction remains a major public health problem today, with 0.3% of the population (855,000 individuals) meeting criteria for abuse or dependence [1] . Despite effective medications for other major drugs of abuse (e.g., alcohol, opiates, nicotine), there is currently no FDA-approved pharmacotherapy for cocaine. Thus, identifying an effective medication for cocaine use disorders is a major public health priority. GLP -1 is an incretin hormone produced by the gut in response to nutrient ingestion [2, 3]. It stimulates pancreatic insulin release and decreases glucose concentrations [4], which led to FDA approval of the GLP-1 analog exenatide (exendin-4 or Byetta) for the treatment of Type 2 Diabetes Mellitus (T2DM). Subsequently, clinical trials demonstrated additional benefits of the drug in promoting decreased food intake, decreased intake of highly palatable food, and weight loss [5-7]. These effects, plus an emerging appreciation of GLP-1's central involvement in brain reward mechanisms motivated the exploration of GLP-1 agonists in models of cocaine effects. These studies showed that pre-treatment with exenatide reduced cocaine's locomotor, neurochemical (i.e., dopamine releasing), and behaviorally rewarding effects [3]. In the current ?proof-of-concept? application, we propose a clinical-translational test of these findings, exploring for the first time in humans the effects of acute (single injection) and subchronic (five-days) pre-treatment with the glucagon like peptide-1 (GLP-1) agonist exenatide on the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug (N=24) using a randomized, within-subject, placebo-controlled, cross-over design. We hypothesize that acute and/or subchronic pretreatment with exenatide will reduce cocaine-induced euphoria and self-regulated cocaine administration (i.e., fewer self-administered cocaine infusions) as compared to placebo. If our hypothesis is confirmed, this study would lead directly to larger scale tests using clinically appropriate GLP-1 agonist formulations (e.g., longer acting, orally available agents now in development) as a new target for treating cocaine dependence. Thus, if successful, the current study will pave the way for a promising new avenue in medications development for treating the disorder.